Hepcidin is an antimicrobial peptide that is synthesized by the liver in response to inflammation and iron overload. Emerging data implicate hepcidin as a major regulator of iron homeostasis in mouse and man. Inappropriate hepcidin expression is associated with diseases such as hereditary hemochromatosis and the anemia of chronic disease. This proposal is designed to test the hypothesis that hepcidin is an essential regulator of iron balance that binds to enterocytes, macrophages, and placental syncytiotrophoblasts where it negatively regulates iron egress. Only in the context of the whole animal can the communication between the immune system and sites of iron storage and utilization be adequately characterized. The Specific Aims of this proposal are: 1) to develop a tetracycline-regulated hepcidin transgenic mouse to investigate the role of hepcidin activity in iron homeostasis and distribution, 2) to determine whether over expression of hepcidin in mice produces a faithful model of the anemia of chronic disease in humans, 3) to identify the putative hepcidin receptor to investigate how hepcidin regulates cellular iron egress. The KO1 award will provide mentored research experience to the candidate under the guidance of Dr. Nancy Andrews, an expert in iron metabolism and mouse genetics. Under Dr. Andrews' mentorship, the candidate will develop the technical skills and the knowledge base necessary for developing transgenic and knock out mice and then testing hypotheses that investigate the physiology of iron metabolism. The candidate will also have the opportunity to develop her reputation as an independent contributor to the field by meeting with prominent scientists, delivering talks, and writing scientific articles about her findings for peer reviewed journals. The KO1 award will facilitate the candidate's transition to an independent research career at the interface of immunology and iron metabolism. Future work will focus on investigating the role of the hepcidin receptor and its homologs in iron metabolism and the anemia of chronic disease